Advanced Science (Sep 2024)
SOX12 Facilitates Hepatocellular Carcinoma Progression and Metastasis through Promoting Regulatory T‐Cells Infiltration and Immunosuppression
- Xiangyuan Luo,
- Wenjie Huang,
- Siwen Li,
- Mengyu Sun,
- Dian Hu,
- Junqing Jiang,
- Zerui Zhang,
- Yijun Wang,
- Yufei Wang,
- Jiaqian Zhang,
- Zhangfan Wu,
- Xiaoyu Ji,
- Danfei Liu,
- Xiaoping Chen,
- Bixiang Zhang,
- Huifang Liang,
- Yiwei Li,
- Bifeng Liu,
- Shuai Wang,
- Xiao Xu,
- Yongzhan Nie,
- Kaichun Wu,
- Daiming Fan,
- Limin Xia
Affiliations
- Xiangyuan Luo
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Wenjie Huang
- Hepatic Surgery Center Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Clinical Medicine Research Center for Hepatic Surgery of Hubei Province Key Laboratory of Organ Transplantation Ministry of Education and Ministry of Public Health Wuhan 430030 China
- Siwen Li
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Mengyu Sun
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Dian Hu
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Junqing Jiang
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Zerui Zhang
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Yijun Wang
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Yufei Wang
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Jiaqian Zhang
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Zhangfan Wu
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Xiaoyu Ji
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Danfei Liu
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Xiaoping Chen
- Hepatic Surgery Center Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Clinical Medicine Research Center for Hepatic Surgery of Hubei Province Key Laboratory of Organ Transplantation Ministry of Education and Ministry of Public Health Wuhan 430030 China
- Bixiang Zhang
- Hepatic Surgery Center Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Clinical Medicine Research Center for Hepatic Surgery of Hubei Province Key Laboratory of Organ Transplantation Ministry of Education and Ministry of Public Health Wuhan 430030 China
- Huifang Liang
- Hepatic Surgery Center Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Clinical Medicine Research Center for Hepatic Surgery of Hubei Province Key Laboratory of Organ Transplantation Ministry of Education and Ministry of Public Health Wuhan 430030 China
- Yiwei Li
- The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics‐Hubei Bioinformatics and Molecular Imaging Key Laboratory Systems Biology Theme Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan 430074 China
- Bifeng Liu
- The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics‐Hubei Bioinformatics and Molecular Imaging Key Laboratory Systems Biology Theme Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan 430074 China
- Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou 310006 China
- Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou 310006 China
- Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi’ an 710032 China
- Kaichun Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi’ an 710032 China
- Daiming Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi’ an 710032 China
- Limin Xia
- Department of Gastroenterology Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato‐Pancreato‐Biliary Diseases Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- DOI
- https://doi.org/10.1002/advs.202310304
- Journal volume & issue
-
Vol. 11,
no. 36
pp. n/a – n/a
Abstract
Abstract Despite the success of immunotherapy in treating hepatocellular carcinoma (HCC), HCC remains a severe threat to health. Here, a crucial transcription factor, SOX12, is revealed that induces the immunosuppression of liver tumor microenvironment. Overexpressing SOX12 in HCC syngeneic models increases intratumoral regulatory T‐cell (Treg) infiltration, decreases CD8+T‐cell infiltration, and hastens HCC metastasis. Hepatocyte‐specific SOX12 knockout attenuates DEN/CCl4‐induced HCC progression and metastasis, whereas hepatocyte‐specific SOX12 knock‐in accelerates these effects. Mechanistically, SOX12 transcriptionally activates C‐C motif chemokine ligand 22 (CCL22) expression to promote the recruitment and suppressive activity of Tregs. Moreover, SOX12 transcriptionally upregulates CD274 expression to suppress CD8+T‐cell infiltration. Either knockdown of CCL22 or PD‐L1 dampens SOX12‐mediated HCC metastasis. Blocking of CC chemokine receptor 4 (CCR4), a receptor for CCL22, by inhibitor C‐021 or Treg‐specific knockout of CCR4 inhibits SOX12‐mediated HCC metastasis. Transforming growth factor‐β1 (TGF‐β1)/TGFβR1‐Smad2/3/4 is identified as a key upstream signaling for SOX12 overexpression in HCC cells. Combining C‐021 or TGFβR1 inhibitor galunisertib with anti‐PD‐L1 exhibits an enhanced antitumor effect in two HCC models. Collectively, the findings demonstrate that SOX12 contributes to HCC immunosuppression through the CCL22/CCR4‐Treg and PD‐L1‐CD8+T axes. Blocking of CCR4 or TGFβR1 improves the efficacy of anti‐PD‐L1 in SOX12‐mediated HCC.
Keywords
